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Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells

Abstract

The influence of acidosis on the expression of the vascular endothelial growth factor (VEGF) gene was determined. FG human pancreatic adenocarcinoma cells were incubated for various time periods in media at a physiologically relevant pH level (6.7–7.4). The expression of VEGF mRNA and protein secretion was inversely correlated with pH in a pH- and time-dependent manner. Transient acidosis also activated the VEGF promoter/enhancer luciferase reporter, which was consistent with an increased VEGF gene transcription rate and VEGF mRNA half-life. These data indicated that acidosis transcriptionally and posttranscriptionally regulates VEGF expression, suggesting that an acidic tumor microenvironment contributes to tumor angiogenesis and progression.

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References

  • Akiri G, Nahari D, Finkelstein Y, Le S, Elroy-Stein O, Levi B . 1998 Oncogene 12: 227–236

  • Bellocq A, Suberville S, Philippe C, Bertrand F, Perez J, Fouqueray B, Cherqui G, Baud L . 1998 J. Biol. Chem. 273: 5086–5092

  • Blancher C, Harris AL . 1998 Cancer Metastasis Rev. 17: 187–194

  • Boucher Y, Baxter LT, Jain RK . 1990 Cancer Res. 50: 4478–4484

  • Brooks SE, Gu X, Kaufmann PM, Marcus DM, Caldwell RB . 1998 Curr. Eye Res. 17: 875–882

  • Claffey KP, Shih SC, Mullen A, Dziennis S, Cusick JL, Abrams KR, Lee SW, Detmar M . 1998 Mol. Biol. Cell 9: 469–481

  • Damert A, Machein M, Breier G, Fujita MQ, Hanahan D, Risau W, Plate KH . 1997 Cancer Res. 57: 3860–3864

  • D'Arcangelo D, Facchiano F, Barlucchi LM, Melillo G, Illi B, Testolin L, Gaetano C, Capogrossi MC . 2000 Circ. Res. 86: 312–318

  • Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y . 1997 Proc. Natl. Acad. Sci. USA 94: 4273–4278

  • Finkenzeller G, Technau A, Marme D . 1995 Biochem. Biophys. Res. Commun. 208: 432–439

  • Flamme I, Frohlich T, Vonreutern M, Kappel A, Damert A, Risau W . 1997 Mech. Dev. 63: 51–60

  • Folkman J . 1996 Nat. Med. 2: 167–168

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL . 1996 Mol. Cell Biol. 16: 4604–4613

  • Griffiths L, Dachs GU, Bicknell R, Harris AL, Stratford IJ . 1997 Cancer Res. 57: 570–572

  • Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M . 1998 EMBO J. 17: 4358–4369

  • Huang S, Robinson JB, DeGuzman A, Bucana CD, Fidler IJ . 2000 Cancer Res. 60: 5334–5339

  • Intaglietta M . 1977 Med. Instrum. 11: 149–152

  • Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Buchler MW, Korc M . 1997 Clin. Cancer Res. 3: 1309–1316

  • Jang A, Hill RP . 1997 Clin. Exp. Metastasis 15: 469–483

  • Kallinowski F, Vaupel P . 1988 Br. J. Cancer 58: 314–321

  • Ladoux A, Frelin C . 1994 Biochem. Biophys. Res. Commun. 204: 794–798

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N . 1989 Science 246: 1306–1309

  • Levy AP, Levy NS, Goldberg MA . 1996 J. Biol. Chem. 271: 25492–25497

  • Liu YX, Cox SR, Morita T, Kourembanas S . 1995 Circ. Res. 77: 638–643

  • Rotin D, Steele-Norwood D, Grinstein S, Tannock I . 1989 Cancer Res. 49: 205–211

  • Scott PA, Gleadie JM, Bicknell R, Harris AL . 1998 Int. J. Cancer 75: 706–712

  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF . 1983 Science 219: 983–985

  • Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K . 1999 Clin. Cancer Res. 5: 7234–7243

  • Shi Q, Le X, Wang B, Xiong Q, Abbruzzese JL, Xie K . 2000 J. Interferon Cytokine Res. 20: 1544–1548

  • Shubik P . 1982 J. Cancer Res. Clin. Oncol. 103: 211–226

  • Shweiki D, Itin A, Soffer D, Keshet E . 1992 Nature (London) 359: 843–845

  • Stein I, Neeman M, Shweiki D, Itin A, Keshet E . 1995 Mol. Cell. Biol. 15: 5363–5368

  • Tannock IF . 1996 J. Clin. Oncol. 14: 3156–3174

  • Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA . 1991 J. Biol. Chem. 266: 11947–11954

  • Vezeridis MP, Doremus CM, Tibbetts LM, Tzanakakis G, Jackson BT . 1989 J. Surg. Oncol. 40: 261–265

  • Vaupel P, Kallinowski F, Okunieff P . 1989 Cancer Res. 49: 6449–6465

  • Wike-Hooley JL, Haveman J, Reinhold HS . 1984 Radiother. Oncol. 2: 343–366

  • Watanabe Y, Miura I, Ohgami Y, Fujiwara M . 1998 Life Sci. 63: 1037–1046

  • Xie K . 2001 Cytokine and Growth Factor Rev. in press

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Acknowledgements

We thank Don Norwood for editorial comments and Judy King for assistance in the preparation of this manuscript. This work was supported in part by the Multidisciplinary Pancreatic Program Research Grant, by Research Project Grant #RPG-00-054-01-CMS from the American Cancer Society, and by Cancer Center Support Core Grant CA16672-23 from the National Cancer Institute (to K Xie).

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Shi, Q., Le, X., Wang, B. et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20, 3751–3756 (2001). https://doi.org/10.1038/sj.onc.1204500

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Keywords

  • angiogenesis
  • VEGF
  • regulation
  • acidosis
  • pancreatic cancer

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